Synergistin derivatives and pharmaceutical compositions which contain them

Abstract

The invention provides new synergistin derivatives of formula <IMAGE> (I) in which Y is hydrogen or dimethylamino and R is a 3- or 4-quinuclidinyl radical, the isomers thereof and their mixtures, and their salts, also the preparation thereof. These compounds may be made by reaction of the corresponding 5-methylene compounds with the appropriate mercaptoquinuclidine. The products of formula (I), optionally combined with pristinamycin IIA or a derivative of pristinamycin IIB of the formula <IMAGE> (II) are useful as antimicrobials.

We claim: 
     
       1. A synergistin of the formula: ##STR72## in which Y is hydrogen or dimethylamino and R is 3- or 4-quinclidinyl, in the form of an isomer or a mixture thereof, and its pharmaceutically acceptable salts. 
     
     
       2. A synergistin according to claim 1 which is 5δ-[(3S)-3-quinuclidinyl]thiomethyl pristinamycin I A , and its pharmaceutically acceptable salts. 
     
     
       3. A synergistin according to claim 1 which is 5δ-[(3R)-3-quinuclidinyl]-thiomethyl pristinamycin I A , and its pharmaceutically acceptable salts. 
     
     
       4. A synergistin according to claim 1 which is 5δ-[(3S)-3-quinuclidinyl]thiomethyl virginiamycin S, and its pharmaceutically acceptable salts. 
     
     
       5. A synergistin according to claim 1 which is 5δ-[(3R)-3-quinuclidinyl]-thiomethyl virginiamycin S, and its pharmaceutically acceptable salts. 
     
     
       6. A pharmaceutical composition useful in the treatment of infections of bacterial origin which contains an effective amount of at least one synergistin as claimed in claim 1, in combination with one or more diluents or adjuvants which are compatible therewith and pharmaceutically acceptable. 
     
     
       7. A pharmaceutical composition useful in the treatment of infections of bacterial origin which contains an effective amount of at least one synergistin as claimed in claim 1 in combination with a synergistic amount of a pristinamycin II A  or a soluble derivative of pristinamycin II B  of formula: ##STR73## in which R 1  denotes (1) an alkylthio radical containing 1 to 5 carbon atoms, substituted by (i) one or two alkylamino or dialkylamino radicals in which each alkyl contains 1 to 5 carbon atoms, and, in a said dialkylamino radical, the two alkyls can form, together with the nitrogen atom to which they are attached, a saturated heterocyclic system chosen from 1-pyrrolidinyl, piperidino, 1-azetidinyl, 1-azepinyl, morpholino, thiomorpholino and 1-piperazinyl (unsubstituted or substituted by alkyl of 1 to 5 carbon atoms); or alternatively   (ii) a 2- or 3-pyrrolidinyl, 2-, 3- or 4-piperidyl, 2- or 3-azetidinyl or 2-, 3- or 4-azepinyl radical;   (2) a radical of formula:   Het--S--        in which Het denotes a 3-pyrrolidinyl, 3- or 4-piperidyl, 3-azetidinyl or 3- or 4-azepinyl radical, unsubstituted or substituted by alkyl of 1 to 5 carbon atoms;   (3) a dialkylamino radical in which each alkyl contains 1 to 10 carbons and the two alkyls can be joined to form, together with the nitrogen atom to which they are attached, a saturated heterocyclic system chosen from 1-pyrrolidinyl, piperidino, 1-azetidinyl, 1-azepinyl, morpholino, thiomorpholino and 1-piperazinyl (unsubstituted or substituted by alkyl of 1 to 5 carbon atoms); or   (4) a radical of formula: ##STR74##  in which R 2  denotes either a heterocyclic radical chosen from 3-azetidinyl, 3-pyrrolidinyl, 3- or 4-piperidyl, or 3- or 4-azepinyl which is unsubstituted or substituted by alkyl of 1 to 10 carbon atoms; or an alkyl chain containing 2 to 4 carbon atoms and substituted by 1 or 2 radicals chosen from phenyl, cycloalkylamino containing 3 to 6 ring atoms and N-alkyl-N-cycloalkylamino containing 1 to 10 carbon atoms in the alkyl and having 3 to 6 ring atoms, alkylamino of 1 to 10 carbon atoms, dialkylamino of 1 to 10 carbon atoms in each alkyl, or di-alkyl-carbamoyloxy of 1 to 10 carbon atoms in each alkyl (the alkyl portions of the latter 2 radicals optionally being able to form, with the nitrogen atom to which they are attached, a heterocyclic radical chosen from 1-azetidinyl, 1-pyrrolidinyl, piperidino, 1-azepinyl, morpholino, thiomorpholino in the sulphoxide or sulphone state, 1-piperazinyl, 4-alkyl-1-piperazinyl having 1 to 10 carbon atoms in the alkyl, N-alkyl-1-homopiperazinyl having 1 to 10 carbon atoms in the alkyl, or 1-imidazolyl, or substituted by one or more heterocyclic radicals chosen from 2-azetidinyl, 2-pyrrolidinyl, 2-piperidyl, 2-azepinyl, piperazinyl, 4-alkyl-piperazinyl having 1 to 10 carbons in the alkyl, quinolyl, isoquinolyl, or imidazolyl, the said radicals being unsubstituted or substituted by alkyl of 1 to 10 carbon atoms, and the said heterocyclic radicals being attached to the chain on which they are carried via a carbon atom, with the proviso that at least one of the substituents carried by the above alkyl chain is a nitrogen-containing substituent capable of forming salts;   (iii) or a [(S)-1-methyl-2-pyrrolidinyl]methyl radical and n is 1 or 2, the alkyl radicals mentioned above being linear or branched;   the said pristinamycin being, where appropriate, in the form of an isomer or mixture thereof and optionally in the form of an acid addition salt.